title: The intratumoral distribution of radiolabeled 177Lu-BR96 monoclonal antibodies changes in relation to tumor histology over time in a syngeneic rat colon carcinoma model.
abstract: The therapeutic effect of radioimmunotherapy depends on the distribution of the absorbed dose in relation to viable cancer cells within the tumor, which in turn is a function of the activity distribution. The aim of this study was to investigate the distribution of (177)Lu-DOTA-BR96 monoclonal antibodies targeting the Lewis Y antigen over 7 d using a syngeneic rat model of colon carcinoma.
  
  
  METHODS
  Thirty-eight tumor-bearing rats were intravenously given 25 or 50 MBq of (177)Lu-DOTA-BR96 per kilogram of body weight and were sacrificed 2, 8, 24, 48, 72, 96, 120, or 168 h after injection, with activity measured in blood and tumor samples. Adjacent cryosections of each tumor were analyzed in 3 ways: imaging using a silicon-strip detector for digital autoradiography, staining for histologic characterization, or staining to determine the distribution of the antigen, vasculature, and proliferating cells using immunohistochemistry. Absorbed-dose rate distribution images at the moment of sacrifice were calculated using the activity distribution and a point-dose kernel. The correlations between antigen expression and both activity uptake and absorbed-dose rate were calculated for several regions of interest in each tumor. Nine additional animals with tumors were given unlabeled antibody to evaluate possible immunologic effects.
  
  
  RESULTS
  At 2-8 h after injection, activity was found in the tumor margins; at 24 h, in viable antigen-expressing areas within the tumor; and at 48 h and later, increasingly in antigen-negative areas of granulation tissue. The correlation between antigen expression and both the mean activity and the absorbed-dose rate in regions of interest changed from positive to negative after 24 h after injection. Antigen-negative areas also increased over time in animals injected with unlabeled BR96, compared with untreated tumors.
  
  
  CONCLUSIONS
  The results indicate that viable Lewis Y-expressing tumor cells are most efficiently treated during the initial uptake period. The activity then seems to remain in these initial uptake regions after the elimination of tumor cells and formation of granulation tissue. Further studies using these techniques could aid in determining the effects of the intratumoral activity distribution on overall therapeutic efficacy.
authors.affiliation: Department of Medical Radiation Physics, Lund University, Lund, Sweden. anders.orbom@med.lu.se
authors.forename: Anders
authors.initials: A
authors.lastname: Örbom
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Eriksson
authors.forename: Erika
authors.initials: E
authors.lastname: Elgström
authors.forename: Tomas
authors.initials: T
authors.lastname: Ohlsson
authors.forename: Rune
authors.initials: R
authors.lastname: Nilsson
authors.forename: Jan
authors.initials: J
authors.lastname: Tennvall
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Strand
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates; D007553:Isotope Labeling; D007983:Lewis Blood Group Antigens / Q000276:immunology / Q000378:metabolism; D008187:Lutetium / Q000627:therapeutic use*; D008297:Male; D009389:Neovascularization, Pathologic; D011829:Radiation Dosage; D011868:Radioisotopes / Q000627:therapeutic use*; D051381:Rats; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; C507851:BR96 monoclonal antibody; D018796:Immunoconjugates; D007983:Lewis Blood Group Antigens; D011868:Radioisotopes; D008187:Lutetium
keywords: 177Lu; autoradiography; dosimetry; intratumoral heterogeneity; radioimmunotherapy